1. Field of the Invention
The present invention relates to treatment of cancer and other tumors in humans, in which x-rays are used to deliver a chemotherapeutic compound in proximity to cancer cells. The invention also relates to a kit useful for such treating; and to compounds, complexes and compositions useful for such treating.
2. Description of the Related Art
In the United States, there are two million new cancer cases each year. About 600,000 patients undergo radiation therapy and almost two million undergo chemotherapy at a cost of well over $100 billion. Both of these therapeutic approaches rely on the increased sensitivity of rapidly dividing cancerous cells to toxic agents. Since the toxic agent is often supplied to the whole body and many normal body tissues are also dividing rapidly (hair roots, cells of the gut lining, etc.) a balance must be achieved between killing the maximum number of cancerous cells while doing the minimum damage to normal body cells. Considerable effort has been made either to maximize this discrimination or to target the toxic agent specifically to the tumor cells. The approach of the invention is designed to overcome the drawbacks inherent in radio- and chemotherapy by using localized delivery of x-rays to activate a compound comprising a chemotherapeutic compound linked to a complex containing an element that can generate ionizing radiation which will disrupt the linkage and release the chemotherapeutic compound. Compounds comprising such elements can be given to the whole body and only activated in the region of the tumor by a narrow, focused beam of specific energy x-rays, to release the chemotherapeutic compound.
Efforts to selectively target cancer cells are disclosed in prior art such as U.S. Pat. No. 5,859,065 which discloses improved therapy by first treating the subject with a compound that inhibits normal cell proliferation while promoting malignant cell proliferation, and then treating with a chemotherapeutic agent; and in U.S. Pat No. 6,366,801 which discloses using compounds having heavy elements to enhance the radiotherapy dose ratio of tumor dose to normal tissue dose. A ratio of up to 10:1 is claimed to be achieved.
U.S. Pat. No. 5,641,764 discloses using halogenated DNA ligands to induce radiation damage in DNA in response to ionizing or ultraviolet (UV) radiation. An iodinated ligand was found to sensitize cell destruction by UV exposure, and the inventors speculate that the ligands may also act as sensitizers of ionizing radiation (from radioactive nuclei or from x-rays).
U.S. Pat. No. 6,224,848 discloses a method of cancer therapy. A compound which binds to the target tissue and contains a gamma radiation absorber isotope is administered. The bound compound is excited by an apparatus using a radiation source consisting of a radioactive isotope or a synchrotron, to release resonant gamma radiation. The gamma radiation is converted internally by the isotope at the target tissue into particle radiation followed by an Auger cascade which is said to damage DNA. Disadvantages of use of a synchrotron source are discussed hereinafter in a section headed “Functional X-Rays”.
An x-ray apparatus in which an e-beam is generated in a tubular chamber and focused on a thin metal foil supported inside the chamber on an end window transparent to x-rays is described in the present applicant's U.S. Pat. No. 5,044,001, the disclosure of which is incorporated herein by reference.
A compact end window, transmission x-ray tube assembly suitable for use in the present invention is disclosed in the present applicant's U.S. Pat. No. 5,627,871, the disclosure of which is incorporated herein by reference. In this x-ray tube, the composition of a thin metal foil target and the energy of an e-beam are selected to generate a microfocused bright beam of x-rays of a pre-selected energy.
Methods for producing taxol and taxol analogs are disclosed, e.g., in U.S. Pat. Nos. 5,675,025, 5,688,977 and 6,307,088.
U.S. Pat. No. 6,191,290 discloses derivatives of taxanes such as paclitaxel (taxol) and taxol analogs conjugated to a receptor ligand peptide, forming a tumor-recognizing conjugate.